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DMRT1 Prevents Female Reprogramming in the Postnatal Mammalian Testis

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DMRT1 Prevents Female Reprogramming in the Postnatal Mammalian Testis LETTER doi:10.1038/nature10239 DMRT1 prevents female reprogramming in the postnatal mammalian testis Clinton K. Matson1,2, Mark W. Murphy1, Aaron L. Sarver3, Michael D. Griswold4, Vivian J. Bardwell1,2,3 & David Zarkower1,2,3 Sex in mammals is determined in the fetal gonad by the presence or expression in Sertoli cells prevents FOXL2 expression and suggest that absence of the Y chromosome gene Sry, which controls whether Dmrt1 mutant testes become feminized during the first postnatal month. bipotential precursor cells differentiate into testicular Sertoli cells Next we examined the timing of FOXL2 induction. At postnatal day or ovarian granulosa cells1. This pivotal decision in a single gonadal (P)7, SCDmrt1KO testes had seminiferous tubules in which all Sertoli cell type ultimately controls sexual differentiation throughout the cells expressed SOX9 normally (Supplementary Fig. 2m–r), but at P14 body. Sex determination can be viewed as a battle for primacy in the fetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving WNT/b-catenin sig- Control ovary Dmrt1–/– (XY) Control testis nalling2. In females the primary sex-determining decision is not a bc final: loss of the FOXL2 transcription factor in adult granulosa cells 2 DAPI can reprogram granulosa cells into Sertoli cells . Here we show that + sexual fate is also surprisingly labile in the testis: loss of the DMRT1 3 transcription factor in mouse Sertoli cells, even in adults, activates FOXL2 Foxl2 and reprograms Sertoli cells into granulosa cells. In this Ad. P28 P28 environment, theca cells form, oestrogen is produced and germ cells SCDmrt1KO(Dhh) SCDmrt1KO(Sf1) GCDmrt1KO(Nanos3) appear feminized. Thus Dmrt1 is essential to maintain mammalian def testis determination, and competing regulatory networks maintain DAPI gonadal sex long after the fetal choice between male and female. + Dmrt1 and Foxl2 are conserved throughout vertebrates4,5 and Dmrt1-related sexual regulators are conserved throughout metazo- FOXL2 ans3. Antagonism between Dmrt1 and Foxl2 for control of gonadal P28 P28 P28 sex may therefore extend beyond mammals. Reprogramming due to Control testis SCDmrt1KO SCDmrt1KO loss of Dmrt1 also may help explain the aetiology of human syn- gj m dromes linked to DMRT1, including disorders of sexual differenti- ation6 and testicular cancer7. Human chromosome 9p deletions removing DMRT1 are associated SOX9 with XY male-to-female sex reversal, and Dmrt1 homologues deter- mine sex in several non-mammalian vertebrates8–10. In mice, Dmrt1 is P14 P14 P28 expressed and required in both germ cells and Sertoli cells of the hkn testis11–13.XYDmrt1-null mutant mice are born as males with testes, although these gonads later undergo abnormal differentiation14; hence the role of Dmrt1 in mammalian sex determination has been unclear FOXL2 (for overview of mammalian sex determination see Supplementary Fig. 1). Here we examine Dmrt1 mutant testes during postnatal P14 P14 P28 development, asking whether loss of Dmrt1 causes postnatal feminiza- ilo DAPI tion in mice. + We first examined gonads of Dmrt1-null mutant males (Dmrt12/2) FOXL2 for the presence of FOXL2, a female-specific transcription factor + expressed in granulosa cells and theca cells15,16, the two somatic cell types of the ovarian follicle (Fig. 1a). Four weeks after birth, abundant SOX9 P14 P14 P28 FOXL2-positive cells were present within mutant seminiferous tubules Figure 1 | DMRT1 maintains SOX9 and suppresses FOXL2 expression in (Fig. 1b), which in control testes contain only germ cells and Sertoli postnatal Sertoli cells. a–c, FOXL2 expression detected by immunofluorescence cells (Fig. 1c). To establish the origin of the FOXL2-positive cells, we in adult (Ad.) granulosa and theca cells of control ovary (a) and intratubular cells deleted Dmrt1 either in germ cells (using Nanos3-cre) or in Sertoli cells ofDmrt1-null testis at P28 (b), but not incontrol testis (c). DAPI, 49,6-diamidino- (using Dhh-cre or Sf1-cre) (Supplementary Fig. 2a–l and Supplemen- 2-phenylindole. d–f, FOXL2 is robustly expressed when Dmrt1 is mutated in fetal Sertoli cells with Dhh-cre (d)orSf1-cre (e) but not when Dmrt1 is mutated in fetal tary Table 1). Loss of Dmrt1 in fetal Sertoli cells (SCDmrt1KO) but not germ cells with Nanos3-cre (f). g–o, Timing of FOXL2 expression. FOXL2 is in fetal germ cells (GCDmrt1KO) induced FOXL2 expression (Fig. 1d–f). absent from control testis at P14 (g–i). Cells expressing FOXL2 or FOXL2 and SCDmrt1KO gonads retained small numbers of germ cells, which SOX9 (arrowheads) are present in SCDmrt1KO testis at P14 (j–l). FOXL2- appeared to arrest in meiotic prophase on the basis of SYCP3 localiza- positive cells are abundant in SCDmrt1KO testis at P28 and most cells no longer tion (Supplementary Fig. 3). These results demonstrate that DMRT1 express SOX9 (m–o). Scale bars, 20 mm. 1Developmental Biology Center and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis 55455, Minnesota, USA. 2Molecular, Cellular, Developmental Biology, and Genetics Graduate Program, University of Minnesota, Minneapolis 55455, Minnesota, USA. 3University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota 55455, USA. 4School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA. 4 AUGUST 2011 | VOL 476 | NATURE | 101 ©2011 Macmillan Publishers Limited. All rights reserved RESEARCH LETTER Control testis Mutant gonad (TX) Mutant gonad (TX) Control ovary aceg DAPI bdf h DAPI + SOX9 + FOXL2 Figure 2 | Sertoli-to-granulosa transdifferentiation in the adult testis. (f, inset). g, h, FOXL2-positive cells in control ovary have DAPI morphology a–h, Expression of FOXL2 and SOX9 one month after tamoxifen (TX) injection similar to FOXL2 single-positive cells of mutant testis. FOXL2-positive cells in into Dmrt1flox/flox adult males (8 weeks and older) carrying inducible ubiquitous mutant testis resemble granulosa cells: they lack the tripartite nucleoli of Sertoli cre transgene UBC-cre/ERT2. a, b, Sertoli cells in control testis express SOX9 cells, have smaller and more rounded nuclei, and have more punctate DAPI but not FOXL2. c–f, Mutant testis has Sertoli-like cells expressing SOX9 or staining. UBC-cre/ERT2 also deletes Dmrt1 in germ cells, causing precocious SOX9 and FOXL2 (d, inset) and granulosa-like cells expressing only FOXL2 meiosis12; after one month germ cells are nearly absent. Scale bars, 20 mm. some intratubular cells co-expressed SOX9 and FOXL2 or lacked cells with typical granulosa cell nuclear morphology that lacked SOX9 SOX9 and strongly expressed FOXL2 (Fig. 1g–l). By P28 few SOX9- and strongly expressed FOXL2 (Fig. 2e–h). Thus antagonism between positive cells remained and most intratubular cells strongly expressed DMRT1 and FOXL2 continues into adulthood and Sertoli cell fate FOXL2 (Fig. 1m–o). Histological analysis of mutant gonads is shown remains plastic even after terminal differentiation. in Supplementary Fig. 4. These results show that fetal loss of Dmrt1 To evaluate further the transformation of mutant gonads, we com- causes postnatal Sertoli cells to lose the male-promoting SOX9 and pared the messenger RNA profile of control and mutant P28 testes; instead express the female-promoting FOXL2. 5,030 mRNAs were expressed .8-fold differently across this data set Loss of Foxl2 in the adult ovary can lead to transdifferentiation of or a data set comparing testis to 21 other tissues including ovary (Sup- granulosa cells to Sertoli cells2, so we asked whether loss of Dmrt1 in plementary Fig. 5a). We calculated Pearson correlation coefficients for the adult testis activates Foxl2 and causes the reciprocal sex trans- expression of these 5,030 mRNAs in mutant gonads relative to each formation, from Sertoli to granulosa. Indeed, one month after deletion tissue and found that the mutant gonad most closely resembled ovary of Dmrt1 in adult males (using a tamoxifen-inducible cre transgene), (Supplementary Fig. 5b; average R 5 0.75). Many mRNAs with we observed cells with typical Sertoli cell features including tripartite decreased expression in mutant gonads also were low in other tissues, nucleoli but expressing both SOX9 and FOXL2 (Fig. 2a–d), as well as probably reflecting a lack of male germ cells, which comprise much of the testis mass. Also, some mRNAs that were increased in mutant a gonads were increased in other tissues. Therefore, to specifically evalu- ate ovary-enriched mRNAs, we used bioGPS (http://www.biogps. gnf.org; see Supplementary Information) to identify 65 mRNAs with ControlSCKO(Dhh) testisSCKO(Sf1)TestisOvaryAdrenalAdiposeES cellsFetusPituitarySem.Thymus vesicleLungPlacentaSpleenMuscleKidneyDiaphramEye Saliv.Heart glandBrainSm. B.intest. marrowLiver expression closely correlated to Foxl2 and then compared their Somatic Oocyte expression in ovary relative to the other 21 tissues (Fig. 3a and Sup- 2 plementary Fig. 6). This comparison confirmed that these mRNAs are 1 highly ovary enriched. About 40% were increased in mutant gonads 0 relative to control testes; about 80% of the remainder were oocyte –1 –2 enriched. Thus loss of Dmrt1 causes large changes in mRNA expres- Ovarian mRNAs sion, including induction of multiple ovary-enriched mRNAs. mRNA profiling of Dmrt1 mutant gonads perinatally and at P9 did not reveal Control ovary Mutant gonad Control testis bc d Figure 3 | Feminization of SCDmrt1KO XY gonads. a, Expression of ovary- enriched mRNAs with expression profiles similar to Foxl2 (see Supplementary Information). mRNAs labelled ‘somatic’ were enriched in ovarian somatic cells; Aromatase those labelled ‘oocyte’ were enriched in female germ cells. See Supplementary Fig. 6 for higher resolution image. B. marrow, bone marrow; Saliv. gland, salivary gland; Sem. vesicle, seminal vesicle; Sm. intestine, small intestine. ef g b–d, Immunohistochemistry detection of CYP19A1/aromatase expression in DAPI + follicles of control adult ovary (a) and in adult XY SCDmrt1KO gonad (b), but only in interstitial Leydig cells of control testis (c). Arrows indicate aromatase- FOXL2 positive granulosa cells in ovary and mutant gonad and negative Sertoli cell in + control testis.
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